CA2810339A1 - Use of c-src inhibitors alone or in combination with sti571 for the treatment of leukaemia - Google Patents
Use of c-src inhibitors alone or in combination with sti571 for the treatment of leukaemia Download PDFInfo
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- CA2810339A1 CA2810339A1 CA2810339A CA2810339A CA2810339A1 CA 2810339 A1 CA2810339 A1 CA 2810339A1 CA 2810339 A CA2810339 A CA 2810339A CA 2810339 A CA2810339 A CA 2810339A CA 2810339 A1 CA2810339 A1 CA 2810339A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/02—Medicinal preparations containing materials or reaction products thereof with undetermined constitution from inanimate materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
The invention relates to a combination which comprises (a) at least one compound decreasing the c-Src activity and (b) N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine or the monomethanesulfonate salt thereof; to pharmaceutical compositions comprising said combinations; and to a method of treating a warm-blooded animal having leukaemia, especially chronic myelogenous leukaemia, comprising administering to the animal at least one compound inhibiting the activity of a member of the Src kinase family, the Tec kinase family or a Raf kinase inhibitor, in particular inhibiting the c-Src protein tyrosine kinase activity or inhibiting simultaneously the c-Src protein tyrosine kinase activity and the Bcr-Abl tyrosine kinase activity, alone or in combination with a Bcr-Abl inhibitor, in particular N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine.
Description
21489-10040D1 =
Use of c-Src inhibitors alone or in combination with STI571 for the treatment of leukaemia This is a divisional application of Canadian Patent Application No. 2,450,777 filed on August 9, 2002. It should be understood that the expression "present invention", or the like, encompass the subject matters of both this divisional application and the parent application.
The invention relates to a method of treating a warm-blooded animal, especially a human, having leukaemia comprising administering to the animal at least one compound inhibiting the c-Src protein tyrosine kinase activity, especially those compounds mentioned herein, in a quantity which is effective against leukaemia; to a method of treating a warm-blooded animal, especially a human, having leukaemia comprising administering to the animal (a) at least one compound decreasing the c-Src activity and (b) N-(544-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylpheny1)-4-(3-pyridy1)-2-pyrimidine-amine (STI571) in a quantity which is jointly therapeutically effective against leukaemia; a combination which comprises (a) at least one compound decreasing the c-Src activity and (b) STI571 or the monomethanesulfonate salt thereof and optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use; a pharmaceutical composition comprising such a combination; the use of a compound inhibiting the c-Src protein tyrosine kinase activity or the use of the combination of (a) and (b) for the preparation of a medicament for the delay of progression or treatment of leukaemia; and to a commercial package or product comprising such a combination of (a) and (b) or at least one compound inhibiting the c-Src protein tyrosine kinase activity together with instructions for use thereof in the treatment of leukaemia.
Protein tyrosine kinases catalyze the phosphorylation of specific tyrosine residues. One member of this class of enzymes is the c-Src protein tyrosine kinase.
Surprisingly, it has now been found that compounds inhibiting the c-Src protein tyrosine kinase activity, especially the compounds described hereinafter, are effective against leukaemia.
Furthermore, it was surprisingly found that the effect in treating leukaemia of a combination which comprises (a) at least one compound decreasing the c-Src activity and (b) STI571 or the monom ethane-sulfonate salt thereof is greater than the effects that can be achieved with either type of combination partner alone, i.e. greater than the effects of a monotherapy using only one of the combination partners (a) and (b) as defined herein.
Hence, in a first embodiment, the present invention relates to a method of treating a warm-blooded animal having leukaemia comprising administering to the animal at least one compound inhibiting the c-Src protein tyrosine kinase activity in a quantity which is , =
Use of c-Src inhibitors alone or in combination with STI571 for the treatment of leukaemia This is a divisional application of Canadian Patent Application No. 2,450,777 filed on August 9, 2002. It should be understood that the expression "present invention", or the like, encompass the subject matters of both this divisional application and the parent application.
The invention relates to a method of treating a warm-blooded animal, especially a human, having leukaemia comprising administering to the animal at least one compound inhibiting the c-Src protein tyrosine kinase activity, especially those compounds mentioned herein, in a quantity which is effective against leukaemia; to a method of treating a warm-blooded animal, especially a human, having leukaemia comprising administering to the animal (a) at least one compound decreasing the c-Src activity and (b) N-(544-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylpheny1)-4-(3-pyridy1)-2-pyrimidine-amine (STI571) in a quantity which is jointly therapeutically effective against leukaemia; a combination which comprises (a) at least one compound decreasing the c-Src activity and (b) STI571 or the monomethanesulfonate salt thereof and optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use; a pharmaceutical composition comprising such a combination; the use of a compound inhibiting the c-Src protein tyrosine kinase activity or the use of the combination of (a) and (b) for the preparation of a medicament for the delay of progression or treatment of leukaemia; and to a commercial package or product comprising such a combination of (a) and (b) or at least one compound inhibiting the c-Src protein tyrosine kinase activity together with instructions for use thereof in the treatment of leukaemia.
Protein tyrosine kinases catalyze the phosphorylation of specific tyrosine residues. One member of this class of enzymes is the c-Src protein tyrosine kinase.
Surprisingly, it has now been found that compounds inhibiting the c-Src protein tyrosine kinase activity, especially the compounds described hereinafter, are effective against leukaemia.
Furthermore, it was surprisingly found that the effect in treating leukaemia of a combination which comprises (a) at least one compound decreasing the c-Src activity and (b) STI571 or the monom ethane-sulfonate salt thereof is greater than the effects that can be achieved with either type of combination partner alone, i.e. greater than the effects of a monotherapy using only one of the combination partners (a) and (b) as defined herein.
Hence, in a first embodiment, the present invention relates to a method of treating a warm-blooded animal having leukaemia comprising administering to the animal at least one compound inhibiting the c-Src protein tyrosine kinase activity in a quantity which is , =
therapeutically effective against leukaemia, in which method said compounds can also be present in the form of their pharmaceutically acceptable salts.
In a second embodiment, the present invention relates to a method of treating a warm-blooded animal having leukaemia comprising administering to the animal (a) at least one compound decreasing the c-Src activity and (b) STI571 in a quantity which is jointly therapeutically effective against leukaemia.
Furthermore, the present invention relates to a combination which comprises (a) at least one compound decreasing the c-Src activity and (b) STI571, wherein the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt, and optionally at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use.
In a broader sense, the present invention relates to a method of treating a warm-blooded animal having leukaemia, in particular comprising administering to the animal at least one compound inhibiting the activity of a member of the Src kinase family, in particular src, yes, hck, fyn, lyn, lck, blk, fgr or Yrk, the activity of a member of the Btk or Tec kinase family or a Rat kinase inhibitOr, e.g. BAY 43-9006, in a quantity which is therapeutically effective against leukaemia alone or in combination with a Bcr-Abl inhibitor, in particular STI571.
The term leukemia as used herein includes, but is not limited to, chronic myelogenous leukaemia (CML) and acute lymphocyte leukaemia (ALL), especially Philadelphia-chromo-some positive acute lymphocyte leukaemia (Ph+ ALL). Preferably, the variant of leukaemia to be treated by the methods disclosed herein is CML.
The term "method of treatment" as used herein includes a treatment effecting the delay of progression of leukemia. The term "delay of progression" as used herein means in particular the administration of a medicament to patients being in a pre-stage or in an early phase of leukaemia, in which patients, for example, a pre-form or an early form of leukaemia is diagnosed or which patients are in a condition, e.g. a condition resulting from an accident, under which it is likely that a corresponding disease will develop.
In a second embodiment, the present invention relates to a method of treating a warm-blooded animal having leukaemia comprising administering to the animal (a) at least one compound decreasing the c-Src activity and (b) STI571 in a quantity which is jointly therapeutically effective against leukaemia.
Furthermore, the present invention relates to a combination which comprises (a) at least one compound decreasing the c-Src activity and (b) STI571, wherein the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt, and optionally at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use.
In a broader sense, the present invention relates to a method of treating a warm-blooded animal having leukaemia, in particular comprising administering to the animal at least one compound inhibiting the activity of a member of the Src kinase family, in particular src, yes, hck, fyn, lyn, lck, blk, fgr or Yrk, the activity of a member of the Btk or Tec kinase family or a Rat kinase inhibitOr, e.g. BAY 43-9006, in a quantity which is therapeutically effective against leukaemia alone or in combination with a Bcr-Abl inhibitor, in particular STI571.
The term leukemia as used herein includes, but is not limited to, chronic myelogenous leukaemia (CML) and acute lymphocyte leukaemia (ALL), especially Philadelphia-chromo-some positive acute lymphocyte leukaemia (Ph+ ALL). Preferably, the variant of leukaemia to be treated by the methods disclosed herein is CML.
The term "method of treatment" as used herein includes a treatment effecting the delay of progression of leukemia. The term "delay of progression" as used herein means in particular the administration of a medicament to patients being in a pre-stage or in an early phase of leukaemia, in which patients, for example, a pre-form or an early form of leukaemia is diagnosed or which patients are in a condition, e.g. a condition resulting from an accident, under which it is likely that a corresponding disease will develop.
The term "compounds inhibiting the c-Src protein tyrosine kinase activity" as used herein means such compounds having an ICso in the range of 1 to 3000 nM, preferably in the range of 1 to 500 nM, in the proliferation test using bcr-Abl transfected 32D cells described hereinafter. The term includes, but is not limited to, compounds belonging to the structure classes of pyrrolopyrimidines, especially pyrrolo[2,3-d]pyrimidines, purines, pyrazo-pyrimidines, especially pyrazo[3,4-d]pyrimidines, pyrazopyrimidines, especially pyrazo[3,4-d]pyrimidines and pyridopyrimidines, especially pyrido[2,3-d]pyrimidines.
Preferably, the term relates to those compounds disclosed in WO 96/10028, WO 97/28161, W097/32879 and W097/49706 and, more preferably, to the single compounds of formulae I to VIII, most preferably to the compound of formula I and V, in particular the compound of formula I.
N
141) o (I) HO HN
JN NN I ) N
(II) WO 03/013540 o CA 02810339 2013-02-11- 4 (III) = HO
N HN 1.1 (IV) NYN
(V) . .
CI Is c5 N
N N NH I CI
(VI) N
HN N N NH
HN o (VII) O
N N I NH
HN Lico =
The compounds which are generically and specifically disclosed in WO 96/10028, WO
97/28161, W097/32879 and W097/49706, in each case in particular in the compound claims and the final products of the working examples.
The compounds can be prepared and administered as described in the cited documents, respectively. The compound of formula I
can be prepared and formulated as described in WO 96/10028. The compound of formula II
and its preparation is disclosed in Example 111c3 of WO 97/16452. The compound of formula IV can be prepared in analogy thereof. Both latter compounds can be formulated as described in WO 97/16452. The compound of formula III is discussed by R. Gamse et al. in J. Bone Miner. Res. 14 (Suppl. 1), 1999, S487. The compound of formula V is also known as PP1. The preparation of PP1 is described by T. Schindler, F. Sicheri et al in Molecular Cell, 1999 (3), 639, 647. The compounds of formula VI, VII and VIII are described in the following documents and the literature cited therein: J.M. Hamby et al, J. Med. Chem.
40, 1997, 2296-2303; R.L. Panek et al, J. Pharmacol. Exp. Ther. 283, 1997, 1433-1444; and S.R. Klutchko et al, J. Med. Chem. 41, 1998, 3276-3292.
STI571 can be prepared and administered as described in WO 99/03854, especially the monomesylate salt of STI571 can be formulated as described in Examples 4 and 6 of WO
99/03854. STI571 can also be administered as marketed under the trademark GLIVECTm or GLEEVECTm.
The term "compounds decreasing the c-Src activity' as used herein includes, but is not limited to, compounds inhibiting the c-Src protein tyrosine kinase activity as defined above and to SH2 interaction inhibitors such as those disclosed in W097/07131 and W097/08193.
Preferably, in the present invention compounds decreasing the c-Src activity are SH2 interaction inhibitors or, more preferably, compounds inhibiting the c-Src protein tyrosine kinase activity as defined above.
It will be understood that references to the pharmacologically active compounds mentioned herein are meant to also include the pharmaceutically acceptable salts. If compounds inhibiting the c-Src protein tyrosine kinase activity or a combination partner (a) or (b) have, for example, at least one basic center, they can form acid addition salts. The combination partners (a) and (b) having an acid group (for example COON) can also form salts with bases. The pharmacologically active compounds mentioned herein may also be used in form of a hydrate or include other solvents used for crystallization. STI571, i.e.
the combination partner (b), is preferably used in the present invention in the form of its monomesylate salt.
Additionally, the present invention relates to a method of treating a warm-blooded animal having leukaemia comprising administering to the animal at least one compound inhibiting the c-Src protein tyrosine kinase activity and the Bcr-Abl tyrosine kinase activity, in a quantity which is therapeutically effective against leukaemia, in which method said compounds can also be present in the form of their pharmaceutically acceptable salts.
Preferably, such compound is a compound of formula V.
The utility of the compounds inhibiting the c-Src protein tyrosine kinase activity for the treatment of leukemia can be demonstrated, e.g., in the proliferation test using bcr-Abl transfected 32D cells as follows:
Bcr-Abl-transfected 32D cells (32D pGD p210 Bcr-Abl; Bazzoni, G.; et al. J.
Clin. Invest.
= (1996), 98(2), 521-528) are cultured in RPM! 1640 (BioConcept, Allschwil, Switzerland; cat.
No.: 1-41F01), 10% fetal calf serum, 2 mM glutamine. 10000 cells in 50 pL per well are seeded into flat bottom 96 well tissue culture plates. Complete medium alone (for controls) or serial threefold dilutions of compounds are added in triplicates to a final volume of 100 pL
and the cells are incubated at 37 C, 5 A CO2 for 65 to 72 h. The cell proliferation reagent WST-1 (Roche Diagnostics GmbH; cat.no.: 1 664 807) is added at 10 pL per well followed by 2 h incubation at 37 C. Colour development, depending on the amount of living cells, is measured at 440 nm. The effect for each compound is calculated as percent inhibition of the value (0D440) obtained for the control cells (100 A) and plotted against the compound concentrations. The ICsos are calculated from the dose response curves by graphic extrapolation.
Compounds inhibiting the growth of 32D-Bcr-Abl cells can be further tested on dependent 32D wt cells to prove the specificity of the compounds for the bcr-Abl kinase and to exclude compound toxicity.
A combination which comprises (a) at least one compound decreasing the c-Src activity and (b) STI571, wherein the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptablesalt, and optionally at least one pharmaceutically acceptable carrier will be referred to hereinafter as a COMBINATION OF THE
INVENTION.
The nature of proliferative diseases like leukemia is multifactorial. Under certain circum-stances, drugs with different mechanisms of action may be combined. However, just considering any combination of drugs having different mode of action does not necessarily lead to combinations with advantageous effects.
All the more surprising is the experimental finding that the administration of a COMBI-NATION OF THE INVENTION, results not only in a beneficial effect, especially a synergistic therapeutic effect, e.g. with regard to slowing down, arresting or reversing the progress of leukaemia or a longer duration of drug response, but also in further surprising beneficial effects, e.g. less side-effects, an improved quality of life and a decreased mortality and morbidity, compared to a monotherapy applying only one of the pharmaceutically active ingredients used in the COMBINATION OF THE INVENTION.
A further benefit is that lower doses of the active ingredients of the COMBINATION OF THE
INVENTION can be used, for example, that the dosages need not only often be smaller, but = can be also applied less frequently, or can be used in order to diminish the incidence of side-effects. This is in accordance with the desires and requirements of the patients to be treated.
The utility of the COMBINATION OF THE INVENTION for the treatment of leukemia can be demonstrated, e.g., in the proliferation test using bcr-Abl transfected 320 cells as follows:
The proliferation test using bcr-Abl transfected 320 cells with a COMBINATION
OF THE
INVENTION is carried out as described above with the following changes. Two combination partners are mixed in fixed ratios. Threefold serial dilutions of this mixture or the combination partners alone are added to the cells seeded in 96 well tissue culture plates as described above. The effects on 32D-bcr-Abl cell proliferation of a COMBINATION OF THE
INVENTION is evaluated and compared with the effects of the single combination partners TM
using CalcuSyn, a dose-effect analyzer software for single and multiple drugs (distributed by TM
Biosoft, Cambridge).
One particular benefit of the present invention is the fact that the leukaemia that can be treated with a compound inhibiting the c-Src protein tyrosine kinase activity or with the COMBINATION OF THE INVENTION can be such leukaemia which is resistent to monotherapy employing STI571 as sole active agent, e.g. leukaemia of such patients who initially had responded to STI571 and then relapsed. Very especially, compounds inhibiting the c-Src protein tyrosine kinase activity and COMBINATIONS OF THE INVENTION
can be used for the treatment of patients in the advanced stage (blast crisis phase) of CML.
The person skilled in the pertinent art is fully enabled to select further relevant test modest to prove the hereinbef ore and hereinafter mentioned beneficial effects on leukaemia of a compound inhibiting the c-Src protein tyrosine kinase activity or of a COMBINATION OF
THE INVENTION. The pharmacological activity of a compound inhibiting the c-Src protein tyrosine kinase activity or a COMBINATION OF THE INVENTION may, for example, be demonstrated in a suitable clinical study. Suitable clinical studies are, for example, open label non-randomized, dose escalation studies in patients with advanced leukaemia. Such studies prove in particular the synergism observed with the COMBINATIONS OF
THE
INVENTION. The beneficial effects on leukaemia can be determined directly through the results of these studies or by changes in the study design which are known as such to a person skilled in the art. For example, the combination partner (b) can be administered with a fixed dose and the dose of the combination partner (a) is escalated until the Maximum Tolerated Dosage is reached. Alternatively, a placebo-controlled, double blind study can be conducted in order to prove the benefits of the COMBINATION OF THE INVENTION
mentioned herein.
In one embodiment of the invention, the compound inhibiting the c-Src protein tyrosine kinase activity is selected from pyrrolopyrimidines, especially pyrrolo[2,3-d]pyrimidines, purines, pyrazopyrimidines, especially pyrazo[3,4-d]pyrimidines, pyrazopyrimidines, especially pyrazo[3,4-d]pyrimidines and pyridopyrimidines, especially pyrido[2,3-d]-pyrimidines. Particularly preferred are the compounds of formula I, II, Ill, IV, V, VI, VII and VIII, especially the compound of formula I and formula V.
Especially preferred is a combination comprising a compound of formula I and STI571 or the pharmaceutically acceptable salts thereof. Furthermore, especially preferred is a combination comprising a compound of formula V and STI571 or the pharmaceutically acceptable salts thereof.
The invention pertains also to the use of at least one compound inhibiting the c-Src protein tyrosine kinase activity or of the COMBINATION OF THE INVENTION for the treatment of leukaemia and for the preparation of a medicament for the treatment of leukaemia.
=
The COMBINATION OF THE INVENTION can be a combined preparation or a pharma-ceutical composition.
The term "a combined preparation", as used herein defines especially a "kit of parts" in the sense that the combination partners (a) and (b) as defined above can be dosed independently or by use of different fixed combinations with distinguished amounts of the combination partners (a) and (b), i.e., simultaneously or at different time points. The parts of the kit of parts can then, e.g., be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts. Very preferably, the time intervals are chosen such that the effect on the treated disease in the combined use of the parts is larger than the effect which would be obtained by = use of only any one of the combination partners (a) and (b). The ratio of the total amounts of the combination partner (a) to the combination partner (b) to be administered in the combined preparation can be varied, e.g. in order to cope with the needs of a patient sub-population to be treated or the needs of the single patient which different needs can be due to the particular disease, age, sex, body weight, etc. of the patients.
Preferably, there is at least one beneficial effect, e.g., a mutual enhancing of the effect of the combination partners (a) and (b), in particular a synergism, e.g. a more than additive effect, additional advantageous effects, less side effects, a combined therapeutical effect in a non-effective dosage of one or both of the combination partners (a) and (b), and very preferably a strong synergism of the combination partners (a) and (b).
It is one objective of this invention to provide a pharmaceutical composition comprising a quantity, which is jointly therapeutically effective against leukaemia comprising the COMBINATION OF THE INVENTION. In this composition, the combination partners (a) and (b) can be administered together, one after the other or separately in one combined unit dosage form or in two separate unit dosage forms. The unit dosage form may also be a fixed combination.
The pharmaceutical compositions for separate administration of the combination partners (a) and (b) and for the administration in a fixed combination, i.e. a single galenical compositions comprising at least two combination partners (a) and (b), according to the invention can be prepared in a manner known per se and are those suitable for enteral, such as oral or rectal, and parenteral administration to mammals (warm-blooded animals), including man, comprising a therapeutically effective amount of at least one pharmacologically active combination partner alone or in combination with one or more pharmaceutically acceptable carries, especially suitable for enteral or parenteral application.
Novel pharmaceutical composition contain, for example, from about 10 % to about 100 %, preferably from about 20 % to about 60 %, of the active ingredients.
Pharmaceutical preparations for the combination therapy for enteral or parenteral administration are, for example, those in unit dosage forms, such as sugar-coated tablets, tablets, capsules or suppositories, and furthermore ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar-coating, dissolving or lyophilizing processes. It will be appreciated that the unit content of a combination partner contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount can be reached by administration of a plurality of dosage units.
In particular, a therapeutically effective amount of each of the combination partner of the COMBINATION OF THE INVENTION may be administered simultaneously or sequentially and in any order, and the components may be administered separately or as a fixed combination. For example, the method of treatment of leukaemia according to the present invention may comprise (i) administration of the combination partner (a) in free or pharmaceutically acceptable salt form and (ii) adminstration of a combination partner (b) in free or pharmaceutically acceptable salt form, simultaneously or sequentially in any order, in jointly therapeutically effective amounts, preferably in synergistically effective amounts, e.g.
in daily dosages corresponding to the amounts described herein. The individual combination partners of the COMBINATION OF THE INVENTION can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. Furthermore, the term administering also encompasses the use of a pro-drug of a combination partner that convert in vivo to the combination partner as such.
The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.
The effective dosage of each of compounds inhibiting the c-Src protein tyrosine kinase activity and of the combination partners employed in the COMBINATION OF THE
INVENTION may vary depending on the particular compound or pharmaceutical composition employed, the mode of administration, the condition being treated, the severity of the condition being treated. Thus, the dosage regimen the COMBINATION OF THE
INVENTION
is selected in accordance with a variety of factors including the route of administration and the renal and hepatic function of the patient. A physician, clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the single active ingredients required to prevent, counter or arrest the progress of the condition. Optimal precision in achieving concentration of the active ingredients within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the active ingredients' availability to target sites.
. N-{544-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylpheny1}-4-(3-pyridy1)-2-pyrimidine-amine monomesylate, is preferably administered to a human in a dosage in the range of about 5 to 850 mg/day, more preferably 25 to 600 mg/day and most preferably 100 to 300 mg/day. Unless stated otherwise herein, the compound is preferably administered from one to four times per day. Compounds inhibiting the c-Src protein tyrosine kinase activity, e.g. the compound of formula I, is preferably administered orally to a human in a dosage in the range of about 100 to 2000 mg/day, more preferably 500 to 1500 mg/day, e.g.
1000 mg/day.
If BAY 43-9006 is employed as a combination partner, it is preferably administered orally at doses of up to 800 mg twice daily.
Moreover, the present invention provides a commercial package comprising as active ingredients COMBINATION OF THE INVENTION, together with instructions for simul-taneous, separate or sequential use thereof in the treatment of leukaemia.
According to an embodiment of the present invention, there is provided use of at least one compound for inhibiting c-Sic protein tyrosine kinase activity or a pharmaceutically acceptable salt thereof for the treatment of chronic myelogenous leukaemia (CML) and/or acute lymphocyte leukaemia (ALL), wherein the CML and ALL are resistant to monotherapy employing N-{544-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylpheny1}-4-(3-pyridy1)-2-pyrimidine-amine as sole active agent.
According to another embodiment of the present invention, there is provided use of at least one compound for inhibiting c-Src protein tyrosine kinase activity and Bcr-Abl tyrosine kinase activity or a pharmaceutically acceptable salt thereof for the treatment of leukaemia, which is resistant to monotherapy employing N-{544-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylpheny1}-4-(3-pyridy1)-2-pyrimidine-amine as sole active agent.
According to still another embodiment of the present invention, there is provided use of at least one compound for inhibiting c-Src protein tyrosine kinase activity or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of chronic myelogenous leukaemia (CML) and/or acute lymphocyte leukaemia (ALL), wherein the CML and ALL are resistant to monotherapy employing N-{544-(4-methyl-piperazino-methyl)-benzoylamidol-2-methylpheny1}-4-(3-pyridy1)-2-pyrimidine-amine as sole active agent.
According to yet another embodiment of the present invention, there is provided use of at least one compound for inhibiting c-Src protein tyrosine kinase activity and Brc-Abl tyrosine kinase activity or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of leukaemia, which is resistant to monotherapy employing N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylpheny1}-4-(3-pyridy1)-2-pyrimidine-amine as sole active agent.
According to a further embodiment of the present invention, there is provided a pharmaceutical composition comprising at least one compound for inhibiting c-Sic protein tyrosine kinase activity or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier for use in the treatment of chronic myelogenous leukaemia (CML) and/or acute lymphocyte leukaemia (ALL), wherein the CML and ALL are resistant to monotherapy employing N-{544-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylpheny1}-4-(3-pyridy1)-2-pyrimidine-amine as sole active agent.
According to yet a further embodiment of the present invention, there is provided a pharmaceutical composition comprising at least one compound for inhibiting c-Src protein tyrosine kinase activity and Brc-Abl tyrosine kinase activity or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier for use in the treatment of leukaemia, which is resistant to monotherapy employing N-{544-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylpheny1}-4-(3-pyridy1)-2-pyrimidine-amine as sole active agent.
According to still a further embodiment of the present invention, there is provided a commercial package comprising at least one c-Src protein tyrosine kinase activity inhibitor together with instructions for use thereof in the treatment of chronic myelogenous leukaemia (CML) and/or acute lymphocyte leukaemia (ALL), wherein the CML and ALL are resistant to monotherapy employing N-{514-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylpheny1}-4-(3-pyridy1)-2-pyrinnidine-amine as sole active agent.
According to another embodiment of the present invention, there is provided a combination which comprises (a) at least one compound for decreasing c-Sic protein tyrosine kinase activity by having an IC50 in the range of 1 to 500 mM, in the proliferation test using bcr-Abl transfected 32D cells, and (b) N-{544-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylpheny1}-4-(3-pyridy1)-2-pyrimidine-amine, wherein the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt, and optionally at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use.
According to still another aspect of the present invention, there is provided use of a combination as described herein for the manufacture of a medicament for use in the treatment of leukaemia.
According to yet another aspect of the present invention, there is provided use of (a) at least one compound for decreasing c-Src activity and (b) N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylpheny1}-4-(3-pyridy1)-2-pyrimidine-amine for the treatment of leukaemia.
According to a further aspect of the present invention, there is provided use of (a) at least one compound for inhibiting c-Src protein tyrosine kinase activity . and (b) N-{544-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylpheny1}-4-(3-pyridyI)-2-pyrimidine-amine in the manufacture of a medicament for use in the treatment of leukaemia.
According to yet a further aspect of the present invention, there is provided a pharmaceutical composition comprising at least one compound for inhibiting c-Src protein tyrosine kinase activity, N-{544-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylpheny1}-4-(3-pyridy1)-2-pyrimidine-amine and at least one pharmaceutically acceptable carrier for use in the treatment of leukaemia.
According to still a further aspect of the present invention, there is provided a pharmaceutical composition comprising a quantity which is jointly therapeutically effective against leukaemia of a combination as described herein and at least one pharmaceutically acceptable carrier.
According to another aspect of the present invention, there is provided a commercial package comprising (a) at least one compound for decreasing c-Src protein tyrosine kinase activity and (b) N-{544-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylpheny1}-4-(3-pyridy1)-2-pyrimidine-amine in free form or in the form of a pharmaceutically acceptable salt, together with instructions for simultaneous, separate or sequential use thereof in the treatment of leukaemia.
Preferably, the term relates to those compounds disclosed in WO 96/10028, WO 97/28161, W097/32879 and W097/49706 and, more preferably, to the single compounds of formulae I to VIII, most preferably to the compound of formula I and V, in particular the compound of formula I.
N
141) o (I) HO HN
JN NN I ) N
(II) WO 03/013540 o CA 02810339 2013-02-11- 4 (III) = HO
N HN 1.1 (IV) NYN
(V) . .
CI Is c5 N
N N NH I CI
(VI) N
HN N N NH
HN o (VII) O
N N I NH
HN Lico =
The compounds which are generically and specifically disclosed in WO 96/10028, WO
97/28161, W097/32879 and W097/49706, in each case in particular in the compound claims and the final products of the working examples.
The compounds can be prepared and administered as described in the cited documents, respectively. The compound of formula I
can be prepared and formulated as described in WO 96/10028. The compound of formula II
and its preparation is disclosed in Example 111c3 of WO 97/16452. The compound of formula IV can be prepared in analogy thereof. Both latter compounds can be formulated as described in WO 97/16452. The compound of formula III is discussed by R. Gamse et al. in J. Bone Miner. Res. 14 (Suppl. 1), 1999, S487. The compound of formula V is also known as PP1. The preparation of PP1 is described by T. Schindler, F. Sicheri et al in Molecular Cell, 1999 (3), 639, 647. The compounds of formula VI, VII and VIII are described in the following documents and the literature cited therein: J.M. Hamby et al, J. Med. Chem.
40, 1997, 2296-2303; R.L. Panek et al, J. Pharmacol. Exp. Ther. 283, 1997, 1433-1444; and S.R. Klutchko et al, J. Med. Chem. 41, 1998, 3276-3292.
STI571 can be prepared and administered as described in WO 99/03854, especially the monomesylate salt of STI571 can be formulated as described in Examples 4 and 6 of WO
99/03854. STI571 can also be administered as marketed under the trademark GLIVECTm or GLEEVECTm.
The term "compounds decreasing the c-Src activity' as used herein includes, but is not limited to, compounds inhibiting the c-Src protein tyrosine kinase activity as defined above and to SH2 interaction inhibitors such as those disclosed in W097/07131 and W097/08193.
Preferably, in the present invention compounds decreasing the c-Src activity are SH2 interaction inhibitors or, more preferably, compounds inhibiting the c-Src protein tyrosine kinase activity as defined above.
It will be understood that references to the pharmacologically active compounds mentioned herein are meant to also include the pharmaceutically acceptable salts. If compounds inhibiting the c-Src protein tyrosine kinase activity or a combination partner (a) or (b) have, for example, at least one basic center, they can form acid addition salts. The combination partners (a) and (b) having an acid group (for example COON) can also form salts with bases. The pharmacologically active compounds mentioned herein may also be used in form of a hydrate or include other solvents used for crystallization. STI571, i.e.
the combination partner (b), is preferably used in the present invention in the form of its monomesylate salt.
Additionally, the present invention relates to a method of treating a warm-blooded animal having leukaemia comprising administering to the animal at least one compound inhibiting the c-Src protein tyrosine kinase activity and the Bcr-Abl tyrosine kinase activity, in a quantity which is therapeutically effective against leukaemia, in which method said compounds can also be present in the form of their pharmaceutically acceptable salts.
Preferably, such compound is a compound of formula V.
The utility of the compounds inhibiting the c-Src protein tyrosine kinase activity for the treatment of leukemia can be demonstrated, e.g., in the proliferation test using bcr-Abl transfected 32D cells as follows:
Bcr-Abl-transfected 32D cells (32D pGD p210 Bcr-Abl; Bazzoni, G.; et al. J.
Clin. Invest.
= (1996), 98(2), 521-528) are cultured in RPM! 1640 (BioConcept, Allschwil, Switzerland; cat.
No.: 1-41F01), 10% fetal calf serum, 2 mM glutamine. 10000 cells in 50 pL per well are seeded into flat bottom 96 well tissue culture plates. Complete medium alone (for controls) or serial threefold dilutions of compounds are added in triplicates to a final volume of 100 pL
and the cells are incubated at 37 C, 5 A CO2 for 65 to 72 h. The cell proliferation reagent WST-1 (Roche Diagnostics GmbH; cat.no.: 1 664 807) is added at 10 pL per well followed by 2 h incubation at 37 C. Colour development, depending on the amount of living cells, is measured at 440 nm. The effect for each compound is calculated as percent inhibition of the value (0D440) obtained for the control cells (100 A) and plotted against the compound concentrations. The ICsos are calculated from the dose response curves by graphic extrapolation.
Compounds inhibiting the growth of 32D-Bcr-Abl cells can be further tested on dependent 32D wt cells to prove the specificity of the compounds for the bcr-Abl kinase and to exclude compound toxicity.
A combination which comprises (a) at least one compound decreasing the c-Src activity and (b) STI571, wherein the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptablesalt, and optionally at least one pharmaceutically acceptable carrier will be referred to hereinafter as a COMBINATION OF THE
INVENTION.
The nature of proliferative diseases like leukemia is multifactorial. Under certain circum-stances, drugs with different mechanisms of action may be combined. However, just considering any combination of drugs having different mode of action does not necessarily lead to combinations with advantageous effects.
All the more surprising is the experimental finding that the administration of a COMBI-NATION OF THE INVENTION, results not only in a beneficial effect, especially a synergistic therapeutic effect, e.g. with regard to slowing down, arresting or reversing the progress of leukaemia or a longer duration of drug response, but also in further surprising beneficial effects, e.g. less side-effects, an improved quality of life and a decreased mortality and morbidity, compared to a monotherapy applying only one of the pharmaceutically active ingredients used in the COMBINATION OF THE INVENTION.
A further benefit is that lower doses of the active ingredients of the COMBINATION OF THE
INVENTION can be used, for example, that the dosages need not only often be smaller, but = can be also applied less frequently, or can be used in order to diminish the incidence of side-effects. This is in accordance with the desires and requirements of the patients to be treated.
The utility of the COMBINATION OF THE INVENTION for the treatment of leukemia can be demonstrated, e.g., in the proliferation test using bcr-Abl transfected 320 cells as follows:
The proliferation test using bcr-Abl transfected 320 cells with a COMBINATION
OF THE
INVENTION is carried out as described above with the following changes. Two combination partners are mixed in fixed ratios. Threefold serial dilutions of this mixture or the combination partners alone are added to the cells seeded in 96 well tissue culture plates as described above. The effects on 32D-bcr-Abl cell proliferation of a COMBINATION OF THE
INVENTION is evaluated and compared with the effects of the single combination partners TM
using CalcuSyn, a dose-effect analyzer software for single and multiple drugs (distributed by TM
Biosoft, Cambridge).
One particular benefit of the present invention is the fact that the leukaemia that can be treated with a compound inhibiting the c-Src protein tyrosine kinase activity or with the COMBINATION OF THE INVENTION can be such leukaemia which is resistent to monotherapy employing STI571 as sole active agent, e.g. leukaemia of such patients who initially had responded to STI571 and then relapsed. Very especially, compounds inhibiting the c-Src protein tyrosine kinase activity and COMBINATIONS OF THE INVENTION
can be used for the treatment of patients in the advanced stage (blast crisis phase) of CML.
The person skilled in the pertinent art is fully enabled to select further relevant test modest to prove the hereinbef ore and hereinafter mentioned beneficial effects on leukaemia of a compound inhibiting the c-Src protein tyrosine kinase activity or of a COMBINATION OF
THE INVENTION. The pharmacological activity of a compound inhibiting the c-Src protein tyrosine kinase activity or a COMBINATION OF THE INVENTION may, for example, be demonstrated in a suitable clinical study. Suitable clinical studies are, for example, open label non-randomized, dose escalation studies in patients with advanced leukaemia. Such studies prove in particular the synergism observed with the COMBINATIONS OF
THE
INVENTION. The beneficial effects on leukaemia can be determined directly through the results of these studies or by changes in the study design which are known as such to a person skilled in the art. For example, the combination partner (b) can be administered with a fixed dose and the dose of the combination partner (a) is escalated until the Maximum Tolerated Dosage is reached. Alternatively, a placebo-controlled, double blind study can be conducted in order to prove the benefits of the COMBINATION OF THE INVENTION
mentioned herein.
In one embodiment of the invention, the compound inhibiting the c-Src protein tyrosine kinase activity is selected from pyrrolopyrimidines, especially pyrrolo[2,3-d]pyrimidines, purines, pyrazopyrimidines, especially pyrazo[3,4-d]pyrimidines, pyrazopyrimidines, especially pyrazo[3,4-d]pyrimidines and pyridopyrimidines, especially pyrido[2,3-d]-pyrimidines. Particularly preferred are the compounds of formula I, II, Ill, IV, V, VI, VII and VIII, especially the compound of formula I and formula V.
Especially preferred is a combination comprising a compound of formula I and STI571 or the pharmaceutically acceptable salts thereof. Furthermore, especially preferred is a combination comprising a compound of formula V and STI571 or the pharmaceutically acceptable salts thereof.
The invention pertains also to the use of at least one compound inhibiting the c-Src protein tyrosine kinase activity or of the COMBINATION OF THE INVENTION for the treatment of leukaemia and for the preparation of a medicament for the treatment of leukaemia.
=
The COMBINATION OF THE INVENTION can be a combined preparation or a pharma-ceutical composition.
The term "a combined preparation", as used herein defines especially a "kit of parts" in the sense that the combination partners (a) and (b) as defined above can be dosed independently or by use of different fixed combinations with distinguished amounts of the combination partners (a) and (b), i.e., simultaneously or at different time points. The parts of the kit of parts can then, e.g., be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts. Very preferably, the time intervals are chosen such that the effect on the treated disease in the combined use of the parts is larger than the effect which would be obtained by = use of only any one of the combination partners (a) and (b). The ratio of the total amounts of the combination partner (a) to the combination partner (b) to be administered in the combined preparation can be varied, e.g. in order to cope with the needs of a patient sub-population to be treated or the needs of the single patient which different needs can be due to the particular disease, age, sex, body weight, etc. of the patients.
Preferably, there is at least one beneficial effect, e.g., a mutual enhancing of the effect of the combination partners (a) and (b), in particular a synergism, e.g. a more than additive effect, additional advantageous effects, less side effects, a combined therapeutical effect in a non-effective dosage of one or both of the combination partners (a) and (b), and very preferably a strong synergism of the combination partners (a) and (b).
It is one objective of this invention to provide a pharmaceutical composition comprising a quantity, which is jointly therapeutically effective against leukaemia comprising the COMBINATION OF THE INVENTION. In this composition, the combination partners (a) and (b) can be administered together, one after the other or separately in one combined unit dosage form or in two separate unit dosage forms. The unit dosage form may also be a fixed combination.
The pharmaceutical compositions for separate administration of the combination partners (a) and (b) and for the administration in a fixed combination, i.e. a single galenical compositions comprising at least two combination partners (a) and (b), according to the invention can be prepared in a manner known per se and are those suitable for enteral, such as oral or rectal, and parenteral administration to mammals (warm-blooded animals), including man, comprising a therapeutically effective amount of at least one pharmacologically active combination partner alone or in combination with one or more pharmaceutically acceptable carries, especially suitable for enteral or parenteral application.
Novel pharmaceutical composition contain, for example, from about 10 % to about 100 %, preferably from about 20 % to about 60 %, of the active ingredients.
Pharmaceutical preparations for the combination therapy for enteral or parenteral administration are, for example, those in unit dosage forms, such as sugar-coated tablets, tablets, capsules or suppositories, and furthermore ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar-coating, dissolving or lyophilizing processes. It will be appreciated that the unit content of a combination partner contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount can be reached by administration of a plurality of dosage units.
In particular, a therapeutically effective amount of each of the combination partner of the COMBINATION OF THE INVENTION may be administered simultaneously or sequentially and in any order, and the components may be administered separately or as a fixed combination. For example, the method of treatment of leukaemia according to the present invention may comprise (i) administration of the combination partner (a) in free or pharmaceutically acceptable salt form and (ii) adminstration of a combination partner (b) in free or pharmaceutically acceptable salt form, simultaneously or sequentially in any order, in jointly therapeutically effective amounts, preferably in synergistically effective amounts, e.g.
in daily dosages corresponding to the amounts described herein. The individual combination partners of the COMBINATION OF THE INVENTION can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. Furthermore, the term administering also encompasses the use of a pro-drug of a combination partner that convert in vivo to the combination partner as such.
The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.
The effective dosage of each of compounds inhibiting the c-Src protein tyrosine kinase activity and of the combination partners employed in the COMBINATION OF THE
INVENTION may vary depending on the particular compound or pharmaceutical composition employed, the mode of administration, the condition being treated, the severity of the condition being treated. Thus, the dosage regimen the COMBINATION OF THE
INVENTION
is selected in accordance with a variety of factors including the route of administration and the renal and hepatic function of the patient. A physician, clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the single active ingredients required to prevent, counter or arrest the progress of the condition. Optimal precision in achieving concentration of the active ingredients within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the active ingredients' availability to target sites.
. N-{544-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylpheny1}-4-(3-pyridy1)-2-pyrimidine-amine monomesylate, is preferably administered to a human in a dosage in the range of about 5 to 850 mg/day, more preferably 25 to 600 mg/day and most preferably 100 to 300 mg/day. Unless stated otherwise herein, the compound is preferably administered from one to four times per day. Compounds inhibiting the c-Src protein tyrosine kinase activity, e.g. the compound of formula I, is preferably administered orally to a human in a dosage in the range of about 100 to 2000 mg/day, more preferably 500 to 1500 mg/day, e.g.
1000 mg/day.
If BAY 43-9006 is employed as a combination partner, it is preferably administered orally at doses of up to 800 mg twice daily.
Moreover, the present invention provides a commercial package comprising as active ingredients COMBINATION OF THE INVENTION, together with instructions for simul-taneous, separate or sequential use thereof in the treatment of leukaemia.
According to an embodiment of the present invention, there is provided use of at least one compound for inhibiting c-Sic protein tyrosine kinase activity or a pharmaceutically acceptable salt thereof for the treatment of chronic myelogenous leukaemia (CML) and/or acute lymphocyte leukaemia (ALL), wherein the CML and ALL are resistant to monotherapy employing N-{544-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylpheny1}-4-(3-pyridy1)-2-pyrimidine-amine as sole active agent.
According to another embodiment of the present invention, there is provided use of at least one compound for inhibiting c-Src protein tyrosine kinase activity and Bcr-Abl tyrosine kinase activity or a pharmaceutically acceptable salt thereof for the treatment of leukaemia, which is resistant to monotherapy employing N-{544-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylpheny1}-4-(3-pyridy1)-2-pyrimidine-amine as sole active agent.
According to still another embodiment of the present invention, there is provided use of at least one compound for inhibiting c-Src protein tyrosine kinase activity or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of chronic myelogenous leukaemia (CML) and/or acute lymphocyte leukaemia (ALL), wherein the CML and ALL are resistant to monotherapy employing N-{544-(4-methyl-piperazino-methyl)-benzoylamidol-2-methylpheny1}-4-(3-pyridy1)-2-pyrimidine-amine as sole active agent.
According to yet another embodiment of the present invention, there is provided use of at least one compound for inhibiting c-Src protein tyrosine kinase activity and Brc-Abl tyrosine kinase activity or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of leukaemia, which is resistant to monotherapy employing N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylpheny1}-4-(3-pyridy1)-2-pyrimidine-amine as sole active agent.
According to a further embodiment of the present invention, there is provided a pharmaceutical composition comprising at least one compound for inhibiting c-Sic protein tyrosine kinase activity or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier for use in the treatment of chronic myelogenous leukaemia (CML) and/or acute lymphocyte leukaemia (ALL), wherein the CML and ALL are resistant to monotherapy employing N-{544-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylpheny1}-4-(3-pyridy1)-2-pyrimidine-amine as sole active agent.
According to yet a further embodiment of the present invention, there is provided a pharmaceutical composition comprising at least one compound for inhibiting c-Src protein tyrosine kinase activity and Brc-Abl tyrosine kinase activity or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier for use in the treatment of leukaemia, which is resistant to monotherapy employing N-{544-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylpheny1}-4-(3-pyridy1)-2-pyrimidine-amine as sole active agent.
According to still a further embodiment of the present invention, there is provided a commercial package comprising at least one c-Src protein tyrosine kinase activity inhibitor together with instructions for use thereof in the treatment of chronic myelogenous leukaemia (CML) and/or acute lymphocyte leukaemia (ALL), wherein the CML and ALL are resistant to monotherapy employing N-{514-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylpheny1}-4-(3-pyridy1)-2-pyrinnidine-amine as sole active agent.
According to another embodiment of the present invention, there is provided a combination which comprises (a) at least one compound for decreasing c-Sic protein tyrosine kinase activity by having an IC50 in the range of 1 to 500 mM, in the proliferation test using bcr-Abl transfected 32D cells, and (b) N-{544-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylpheny1}-4-(3-pyridy1)-2-pyrimidine-amine, wherein the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt, and optionally at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use.
According to still another aspect of the present invention, there is provided use of a combination as described herein for the manufacture of a medicament for use in the treatment of leukaemia.
According to yet another aspect of the present invention, there is provided use of (a) at least one compound for decreasing c-Src activity and (b) N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylpheny1}-4-(3-pyridy1)-2-pyrimidine-amine for the treatment of leukaemia.
According to a further aspect of the present invention, there is provided use of (a) at least one compound for inhibiting c-Src protein tyrosine kinase activity . and (b) N-{544-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylpheny1}-4-(3-pyridyI)-2-pyrimidine-amine in the manufacture of a medicament for use in the treatment of leukaemia.
According to yet a further aspect of the present invention, there is provided a pharmaceutical composition comprising at least one compound for inhibiting c-Src protein tyrosine kinase activity, N-{544-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylpheny1}-4-(3-pyridy1)-2-pyrimidine-amine and at least one pharmaceutically acceptable carrier for use in the treatment of leukaemia.
According to still a further aspect of the present invention, there is provided a pharmaceutical composition comprising a quantity which is jointly therapeutically effective against leukaemia of a combination as described herein and at least one pharmaceutically acceptable carrier.
According to another aspect of the present invention, there is provided a commercial package comprising (a) at least one compound for decreasing c-Src protein tyrosine kinase activity and (b) N-{544-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylpheny1}-4-(3-pyridy1)-2-pyrimidine-amine in free form or in the form of a pharmaceutically acceptable salt, together with instructions for simultaneous, separate or sequential use thereof in the treatment of leukaemia.
Claims (26)
1. A combination which comprises (a) at least one compound for decreasing c-Src protein tyrosine kinase activity by having an IC50 in the range of 1 to 500 mM, in the proliferation test using bcr-Abl transfected 32D cells, and (b) N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine, wherein the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt, and optionally at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use.
2. The combination according to claim 1 wherein the at least one compound for decreasing c-Src protein tyrosine kinase activity is a compound of formula I:
3. The combination according to claim 1 wherein the at least one compound for decreasing c-Src protein tyrosine kinase activity is a compound of formula II:
4. The combination according to claim 1 wherein the at least one compound for decreasing c-Src protein tyrosine kinase activity is a compound of formula III:
5. The combination according to claim 1 wherein the at least one compound for decreasing c-Src protein tyrosine kinase activity is a compound of formula IV:
6. The combination according to claim 1 wherein the at least one compound for decreasing c-Src protein tyrosine kinase activity is a compound of formula V:
7. The combination according to claim 1 wherein the at least one compound for decreasing c-Src protein tyrosine kinase activity is a compound of formula VI:
8. The combination according to claim 1 wherein the at least one compound for decreasing c-Src protein tyrosine kinase activity is a compound of formula VII:
9. The combination according to claim 1 wherein the at least one compound for decreasing c-Src protein tyrosine kinase activity is a compound of formula VIII:
10. The combination according to any one of claims 1 to 9 wherein compound (b) is used in the form of its monomethanesulfonate salt.
11. The combination according to any one of claims 1 to 10 for use in the therapeutic or diagnostic treatment of an animal or human body.
12. Use of a combination according to any one of claims 1 to 10 for the manufacture of a medicament for use in the treatment of leukaemia.
13. Use of (a) at least one compound for decreasing c-Src activity and (b) N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine for the treatment of leukaemia.
14. The use according to claim 13, wherein the compound for decreasing c-Src protein tyrosine kinase activity is a compound of formula I:
or a compound of formula V:
or a compound of formula V:
15. The use according to claim 13 or 14 wherein said leukaemia is resistant to mono-therapy employing N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine as sole active agent.
16. The use according to claim 13 or 14 wherein said leukaemia is chronic myelogenous leukaemia.
17. Use of (a) at least one compound for inhibiting c-Src protein tyrosine kinase activity and (b) N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine in the manufacture of a medicament for use in the treatment of leukaemia.
18. The use according to claim 17, wherein the compound for decreasing c-Src protein tyrosine kinase activity is a compound of formula I:
or a compound of formula V:
or a compound of formula V:
19. The use according to claim 17 or 18 wherein said leukaemia is resistant to mono-therapy employing N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine as sole active agent.
20. The use according to claim 17 or 18 wherein said leukaemia is chronic myelogenous leukaemia.
21. A pharmaceutical composition comprising at least one compound for inhibiting c-Src protein tyrosine kinase activity, N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine and at least one pharmaceutically acceptable carrier for use in the treatment of leukaemia.
22. The pharmaceutical composition according to claim 21, wherein the compound for decreasing the c-Src protein tyrosine kinase activity is a compound of formula I:
or a compound of formula V:
or a compound of formula V:
23. The pharmaceutical composition according to claim 21 or 22 wherein said leukaemia is resistant to mono-therapy employing N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine as sole active ingredient.
24. The pharmaceutical composition according to claim 21 or 22 wherein said leukaemia is chronic myelogenous leukaemia.
25. A pharmaceutical composition comprising a quantity which is jointly therapeutically effective against leukaemia of a combination according to any one of claims 1 to 10 and at least one pharmaceutically acceptable carrier.
26. A commercial package comprising (a) at least one compound for decreasing c-Src protein tyrosine kinase activity and (b) N-{5-[4-(4-methyl-piperazino-ethyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine in free form or in the form of a pharmaceutically acceptable salt, together with instructions for simultaneous, separate or sequential use thereof in the treatment of leukaemia.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US31169001P | 2001-08-10 | 2001-08-10 | |
| US60/311,690 | 2001-08-10 | ||
| CA2450777A CA2450777C (en) | 2001-08-10 | 2002-08-09 | Use of c-src inhibitors alone or in combination with sti571 for the treatment of leukaemia |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2450777A Division CA2450777C (en) | 2001-08-10 | 2002-08-09 | Use of c-src inhibitors alone or in combination with sti571 for the treatment of leukaemia |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2810339A1 true CA2810339A1 (en) | 2003-02-20 |
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| CA2450777A Expired - Fee Related CA2450777C (en) | 2001-08-10 | 2002-08-09 | Use of c-src inhibitors alone or in combination with sti571 for the treatment of leukaemia |
| CA2810339A Abandoned CA2810339A1 (en) | 2001-08-10 | 2002-08-09 | Use of c-src inhibitors alone or in combination with sti571 for the treatment of leukaemia |
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| CA2450777A Expired - Fee Related CA2450777C (en) | 2001-08-10 | 2002-08-09 | Use of c-src inhibitors alone or in combination with sti571 for the treatment of leukaemia |
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| EP (2) | EP2258371A1 (en) |
| JP (1) | JP2005502643A (en) |
| CN (1) | CN1523991A (en) |
| CA (2) | CA2450777C (en) |
| WO (1) | WO2003013540A1 (en) |
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| US7125875B2 (en) | 1999-04-15 | 2006-10-24 | Bristol-Myers Squibb Company | Cyclic protein tyrosine kinase inhibitors |
| JP2005526008A (en) * | 2001-12-04 | 2005-09-02 | オニックス ファーマシューティカルズ，インコーポレイティド | RAF-MEK-ERK pathway inhibitors for treating cancer |
| CL2003002287A1 (en) | 2002-11-25 | 2005-01-14 | Wyeth Corp | COMPOUNDS DERIVED FROM TIENO [3,2-b] -PIRIDINA-6-CARBONITRILOS AND TIENEO [2,3-b] -PIRIDINA-5-CARBONITRILS, PHARMACEUTICAL COMPOSITION, PROCEDURE OF PREPARATION AND INTERMEDIARY COMPOUNDS, AND THEIR USE IN THE TREATMENT OF CANCER, APOPLEJIA, OSTEOPOROSIS |
| US7276519B2 (en) | 2002-11-25 | 2007-10-02 | Wyeth | Thieno[3,2-b]pyridine-6-carbonitriles and thieno[2,3-b]pyridine-5-carbonitriles as protein kinase inhibitors |
| US20050009891A1 (en) | 2003-07-09 | 2005-01-13 | Lee Francis Y. | Combination of SRC Kinase inhibitors and chemotherapeutic agents for the treatment of proliferative diseases |
| US7750160B2 (en) | 2003-11-13 | 2010-07-06 | Ambit Biosciences Corporation | Isoxazolyl urea derivatives as kinase modulators |
| WO2005063720A1 (en) * | 2003-12-25 | 2005-07-14 | Nippon Shinyaku Co., Ltd. | Amide derivative and medicine |
| EP1713806B1 (en) * | 2004-02-14 | 2013-05-08 | Irm Llc | Compounds and compositions as protein kinase inhibitors |
| EP1763345A2 (en) | 2004-06-18 | 2007-03-21 | GPC Biotech Inc. | Kinase inhibitors for treating cancers |
| AU2005309019A1 (en) * | 2004-11-24 | 2006-06-01 | Novartis Ag | Combinations of JAK inhibitors and at least one of Bcr-Abl, Flt-3, FAK or RAF kinase inhibitors |
| EP1955073A2 (en) * | 2005-11-15 | 2008-08-13 | Brystol-Myers Squibb Company | Methods of identifying and treating individuals exhibiting mdr-1 overexpression with protein tyrosine kinase inhibitors and combinations thereof |
| US20090306094A1 (en) * | 2006-03-17 | 2009-12-10 | Bristol-Myers Squibb Company | Methods Of Identifying And Treating Individuals Exhibiting Mutant Bcr/Abl Kinase Polypeptides |
| CA2644841C (en) * | 2006-04-07 | 2013-07-16 | Novartis Ag | Use of c-src inhibitors in combination with a pyrimidylaminobenzamide compound for the treatment of leukemia |
| EP2081435B1 (en) | 2006-09-22 | 2016-05-04 | Pharmacyclics LLC | Inhibitors of bruton's tyrosine kinase |
| US20100173426A1 (en) * | 2006-12-19 | 2010-07-08 | Johnson Faye M | Biomaker identifying the reactivation of stat3 after src inhibition |
| EP2560007A1 (en) * | 2007-03-28 | 2013-02-20 | Pharmacyclics, Inc. | Identification of bruton's tyrosine kinase inhibitors |
| US20120101113A1 (en) | 2007-03-28 | 2012-04-26 | Pharmacyclics, Inc. | Inhibitors of bruton's tyrosine kinase |
| JP2011503103A (en) * | 2007-11-07 | 2011-01-27 | フォールドアールエックス ファーマシューティカルズ インコーポレーティッド | Methods for regulating protein transport |
| EP3311818A3 (en) | 2008-07-16 | 2018-07-18 | Pharmacyclics, LLC | Inhibitors of bruton's tyrosine kinase for the treatment of solid tumors |
| WO2011153514A2 (en) | 2010-06-03 | 2011-12-08 | Pharmacyclics, Inc. | The use of inhibitors of bruton's tyrosine kinase (btk) |
| WO2013010136A2 (en) | 2011-07-13 | 2013-01-17 | Pharmacyclics, Inc. | Inhibitors of bruton's tyrosine kinase |
| US8377946B1 (en) | 2011-12-30 | 2013-02-19 | Pharmacyclics, Inc. | Pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine compounds as kinase inhibitors |
| JP6182593B2 (en) * | 2012-04-20 | 2017-08-16 | アドヴィーナス セラピューティクス リミテッド | Substituted heterobicyclic compounds, compositions and medicaments and uses thereof |
| IN2014MN02338A (en) * | 2012-05-31 | 2015-08-14 | Pharmascience Inc | |
| NZ702548A (en) | 2012-06-04 | 2015-11-27 | Pharmacyclics Llc | Crystalline forms of a bruton’s tyrosine kinase inhibitor |
| JP6575950B2 (en) | 2012-07-24 | 2019-09-18 | ファーマサイクリックス エルエルシー | Mutations with resistance to Bruton tyrosine kinase (Btk) inhibitors |
| MX2015006168A (en) | 2012-11-15 | 2015-08-10 | Pharmacyclics Inc | Pyrrolopyrimidine compounds as kinase inhibitors. |
| US10144828B2 (en) | 2012-11-21 | 2018-12-04 | Stratasys, Inc. | Semi-crystalline build materials |
| JP6800750B2 (en) | 2013-08-02 | 2020-12-16 | ファーマサイクリックス エルエルシー | Treatment method for solid tumors |
| CA2920534A1 (en) | 2013-08-12 | 2015-02-19 | Pharmacyclics Llc | Methods for the treatment of her2 amplified cancer |
| PE20160560A1 (en) | 2013-09-30 | 2016-06-09 | Pharmacyclics Llc | DERIVATIVES OF PIRAZOLO [3,4-d] PYRIMIDIN AS IRREVERSIBLE INHIBITORS OF BRUTON TYROSINE KINASE (BTK) |
| US9885086B2 (en) | 2014-03-20 | 2018-02-06 | Pharmacyclics Llc | Phospholipase C gamma 2 and resistance associated mutations |
| US9533991B2 (en) | 2014-08-01 | 2017-01-03 | Pharmacyclics Llc | Inhibitors of Bruton's tyrosine kinase |
| JP2017523206A (en) | 2014-08-07 | 2017-08-17 | ファーマサイクリックス エルエルシー | New formulation of breton-type tyrosine kinase inhibitor |
| BR122023020985A2 (en) | 2015-03-03 | 2023-12-26 | Pharmacyclics Llc | SOLID TABLET FORMULATION OF A BRUTON'S TYROSINE KINASE INHIBITOR |
| US10722484B2 (en) | 2016-03-09 | 2020-07-28 | K-Gen, Inc. | Methods of cancer treatment |
| CN108101905A (en) * | 2016-11-24 | 2018-06-01 | 中国科学院上海药物研究所 | Pyrimido [5,4-b] indolizine or pyrimido [5,4-b] pyrrole biopterin compound, preparation method and the usage |
| WO2019108677A1 (en) | 2017-11-29 | 2019-06-06 | Adaptive Phage Therapeutics, Inc. | Methods of vaccination using icosahedral phage |
| TW202200589A (en) * | 2020-05-28 | 2022-01-01 | 瑞士商諾華公司 | Mll1 inhibitors and anti-cancer agents |
| WO2021252450A1 (en) | 2020-06-08 | 2021-12-16 | Adaptive Phage Therapeutics, Inc. | Phage display vaccine for covid-19 using a novel peptide sequence |
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| EP0682027B1 (en) * | 1994-05-03 | 1997-10-15 | Novartis AG | Pyrrolopyrimidine derivatives with antiproliferative action |
| ATE199553T1 (en) | 1994-09-29 | 2001-03-15 | Novartis Erfind Verwalt Gmbh | PYRROLO(2,3-D)PYRIMIDINE DERIVATIVES AND THEIR USE |
| GB9516842D0 (en) | 1995-08-17 | 1995-10-18 | Ciba Geigy Ag | Various acylated oligopeptides |
| GB9517060D0 (en) | 1995-08-17 | 1995-10-25 | Ciba Geigy Ag | Acylated oligopeptide derivatives |
| PT874846E (en) * | 1995-11-01 | 2003-08-29 | Novartis Ag | PURINA DERIVATIVES AND PROCESSES FOR THEIR PREPARATION |
| CH690773A5 (en) | 1996-02-01 | 2001-01-15 | Novartis Ag | Pyrrolo (2,3-d) pyrimides and their use. |
| AU1794697A (en) | 1996-03-06 | 1997-09-22 | Novartis Ag | 7-alkyl-pyrrolo{2,3-d}pyrimidines |
| AU3176297A (en) | 1996-06-25 | 1998-01-14 | Novartis Ag | Substituted 7-amino-pyrrolo{3,2-d}pyrimidines and the use thereof |
| CO4940418A1 (en) | 1997-07-18 | 2000-07-24 | Novartis Ag | MODIFICATION OF A CRYSTAL OF A DERIVATIVE OF N-PHENYL-2-PIRIMIDINAMINE, PROCESSES FOR ITS MANUFACTURE AND USE |
| US6100254A (en) * | 1997-10-10 | 2000-08-08 | Board Of Regents, The University Of Texas System | Inhibitors of protein tyrosine kinases |
| US7125875B2 (en) | 1999-04-15 | 2006-10-24 | Bristol-Myers Squibb Company | Cyclic protein tyrosine kinase inhibitors |
| RU2312860C2 (en) | 1999-04-15 | 2007-12-20 | Бристол-Маерс Сквибб Компани | Cyclic inhibitors of protein-tyrosine kinase |
| US20050215795A1 (en) | 2004-02-06 | 2005-09-29 | Bang-Chi Chen | Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors |
| TWI338004B (en) | 2004-02-06 | 2011-03-01 | Bristol Myers Squibb Co | Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors |
-
2002
- 2002-08-09 CN CNA028136969A patent/CN1523991A/en active Pending
- 2002-08-09 EP EP10175362A patent/EP2258371A1/en not_active Withdrawn
- 2002-08-09 EP EP02794592A patent/EP1418917A1/en not_active Withdrawn
- 2002-08-09 WO PCT/EP2002/008941 patent/WO2003013540A1/en active Application Filing
- 2002-08-09 JP JP2003518549A patent/JP2005502643A/en not_active Withdrawn
- 2002-08-09 US US10/485,803 patent/US20040248906A1/en not_active Abandoned
- 2002-08-09 CA CA2450777A patent/CA2450777C/en not_active Expired - Fee Related
- 2002-08-09 CA CA2810339A patent/CA2810339A1/en not_active Abandoned
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2005
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2006
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Also Published As
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| EP2258371A1 (en) | 2010-12-08 |
| EP1418917A1 (en) | 2004-05-19 |
| US20070027167A1 (en) | 2007-02-01 |
| CA2450777A1 (en) | 2003-02-20 |
| US20070149539A1 (en) | 2007-06-28 |
| US8268837B2 (en) | 2012-09-18 |
| US20060074094A1 (en) | 2006-04-06 |
| US8119649B2 (en) | 2012-02-21 |
| CN1523991A (en) | 2004-08-25 |
| CA2450777C (en) | 2013-04-09 |
| US20040248906A1 (en) | 2004-12-09 |
| JP2005502643A (en) | 2005-01-27 |
| US20090227608A1 (en) | 2009-09-10 |
| WO2003013540A1 (en) | 2003-02-20 |
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